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Publication Detail

Title: Soluble epoxide hydrolase is an endogenous regulator of obesity-induced intestinal barrier dysfunction and bacterial translocation.

Authors: Wang, Yuxin; Yang, Jun; Wang, Weicang; Sanidad, Katherine Z; Cinelli, Maris A; Wan, Debin; Hwang, Sung Hee; Kim, Daeyoung; Lee, Kin Sing Stephen; Xiao, Hang; Hammock, Bruce D; Zhang, Guodong

Published In Proc Natl Acad Sci U S A, (2020 04 14)

Abstract: Intestinal barrier dysfunction, which leads to translocation of bacteria or toxic bacterial products from the gut into bloodstream and results in systemic inflammation, is a key pathogenic factor in many human diseases. However, the molecular mechanisms leading to intestinal barrier defects are not well understood, and there are currently no available therapeutic approaches to target intestinal barrier function. Here we show that soluble epoxide hydrolase (sEH) is an endogenous regulator of obesity-induced intestinal barrier dysfunction. We find that sEH is overexpressed in the colons of obese mice. In addition, pharmacologic inhibition or genetic ablation of sEH abolishes obesity-induced gut leakage, translocation of endotoxin lipopolysaccharide or bacteria, and bacterial invasion-induced adipose inflammation. Furthermore, systematic treatment with sEH-produced lipid metabolites, dihydroxyeicosatrienoic acids, induces bacterial translocation and colonic inflammation in mice. The actions of sEH are mediated by gut bacteria-dependent mechanisms, since inhibition or genetic ablation of sEH fails to attenuate obesity-induced gut leakage and adipose inflammation in mice lacking gut bacteria. Overall, these results support that sEH is a potential therapeutic target for obesity-induced intestinal barrier dysfunction, and that sEH inhibitors, which have been evaluated in human clinical trials targeting other human disorders, could be promising agents for prevention and/or treatment.

PubMed ID: 32220957 Exiting the NIEHS site

MeSH Terms: Adipose Tissue/immunology; Animals; Bacteria/genetics; Bacteria/isolation & purification; Bacterial Physiological Phenomena; Bacterial Translocation*; Epoxide Hydrolases/genetics; Epoxide Hydrolases/immunology*; Gastrointestinal Microbiome; Humans; Intestinal Diseases/enzymology*; Intestinal Diseases/etiology; Intestinal Diseases/immunology; Intestinal Diseases/microbiology; Intestines/enzymology*; Intestines/immunology; Intestines/microbiology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity/complications*; Obesity/enzymology; Obesity/genetics

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